Rheumatoid arthritis is a chronic inflammatory disease in which the synovial membrane is the primary site of inflammation. Bone destruction occurs with the progression of inflammation, resulting in deformation or damage of bones and cartilages. Rheumatoid arthritis sometimes develops into a wasting disease accompanying not only inflammation of synovial membranes or osteoarticular tissues, but also systemic inflammation, causing disorders in various organs and tissues, and may even lead to severe symptoms affecting life prognosis.
Rheumatoid arthritis is considered to develop as a result of the complex involvement of many factors, and the mechanism of its onset has not been fully elucidated. However, clinical observations have shown villous hyperplasia of synovial membranes with angiogenesis, and infiltration of inflammatory cells (lymphocytes and macrophages) that produce various inflammatory cytokines or growth factors, into synovial tissues. Accordingly, the various arthritic symptoms of rheumatoid arthritis are thought to arise due to the close involvement of infiltrating inflammatory cell activation in synovial membranes. Furthermore, bone and articular tissues of rheumatoid arthritis patients show villous-like proliferated synovial membranes invading and destroying articular tissues, mainly bone tissues. Thus, villous proliferation of the synovial membrane is considered to be a direct cause of inflammation-associated paraarticular osteoporosis and damage to articular function (support, mobility, and indolence).
In Japan, the number of patients with arthritis, in particular rheumatoid arthritis, is said to have reached over 700,000. Since rheumatoid arthritis develops in people in their thirties and forties and gradually becomes advanced and aggravated during the middle to old age, it significantly affects daily life. Therefore, vigorous research and development of anti-rheumatic agents have been carried out in and outside of Japan. In recent years, anti-cytokine therapies targeting inflammatory cytokines have been receiving attention, and novel biopharmaceuticals having effective anti-rheumatic actions, such as infliximab, etanercept, anakinra, and atlizumab, have been developed.
However, even superior anti-rheumatic agents are not effective for all patients, and there are always responders and non-responders to each type of anti-rheumatic agent. Moreover, due to long-term administration of a pharmaceutical agent, even responders often show a resistance effect (reduced drug efficacy), thereby requiring increased dosage of the agent or a switch to another agent. Furthermore, complications or past illnesses of a patient may often limit the administration of anti-rheumatic agents. To rescue patients non-responsive to conventional anti-rheumatic agents and those cases that do not allow the administration of anti-rheumatic agents due to complications, development of novel anti-rheumatic agents is still very much in need.
As rheumatoid arthritis progresses, bone destruction takes place. Bone destruction is mediated by osteoclasts. Osteoclasts differentiate from bone marrow monocyte/macrophage lineage precursor cells, and the RANKL (receptor activator of NF-κB ligand)-RANK signal is known to be deeply involved in inducing the differentiation. RANKL was initially reported as a dendritic cell activator, but was later found to be identical to osteoclast differentiation factor (ODF) expressed in osteoclastogenesis-supporting cells. RANKL is a type II transmembrane protein belonging to the TNF ligand family, but it is also produced as the soluble type by cleavage of the membrane type by a metalloprotease. Both the membrane-type RANKL and the soluble-type RANKL exist as homotrimers, and act as agonists against RANK (receptor activator of NF-κB). RANKL is induced by IL-1, IL-6, TNF-α, and such, and is expressed in osteoblasts, synovial fibroblasts, activated T-cells, etc. RANK, a receptor of RANKL, is a type I membrane protein expressed in dendritic cells, osteoclast precursor cells, and such, and has binding sites for Traf1, 2, 3, 5, and 6 in its intracellular domain. When RANKL binds to RANK on an osteoclast precursor cell, the RANKL-RANK signal is transmitted downstream to Traf 6, NF-κB, JNK, p38, and such, and osteoclast differentiation is induced. Recently, it has been successively reported that reactive oxygen species (ROS) play an important role in RANKL signal-mediated osteoclast differentiation (Non-Patent Documents 1-4).
While the etiology of rheumatoid arthritis is closely associated with inflammatory cytokines (TNF-α, IL-1, IL-6, and such) produced mainly by macrophages, reactive oxygen species are involved in activating lymphocytes that induce the activation of these macrophages (Non-Patent Document 5). Furthermore, it is known that intracellular production of reactive oxygen species increases with stimulation by TNF-α, IL-1, IL-6, or such, and that reactive oxygen species play an important role as messengers in the intracellular signal transduction pathway (NFkB, P38, and PI-3 kinase) (Non-Patent Documents 6-7).
On the other hand, excessively produced, high concentrations of reactive oxygen species induce cytotoxicity or cell death. This means that scavenging excessive reactive oxygen species leads to suppression of cell activity decrease, suppression of cell aging and death, and prolongation of the life span of cells. Thus, if the cell death or cell activity decrease of inflammatory cytokine-producing cells is suppressed by scavenging reactive oxygen, cell activities (induction of cytokine production, and differentiation and maturation of osteoclasts) will increase as a result, and consequently, this may lead to aggravation of rheumatic diseases. In fact, increase in intracellular reactive oxygen has been reported to cause cellular aging and decreased cell activity of hematopoietic stem cells through the cell signaling pathway mediated by p38 kinase (Non-Patent Document 8). This finding suggests the possibility that scavenging reactive oxygen species may lead to the suppression of aging and the activation of cells.
Accordingly, reactive oxygen is deeply involved in intracellular signal transduction, and may regulate life activities by having both positive and negative effects on cells. Which of the opposing effects of reactive oxygen become dominant may depend on the characteristics and environment of respective cells receiving those effects, and therefore cannot be definitely conceived.
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